Spinal cord injury (SCI) is a devastating trauma which results in functional impairments varying from motor and sensory dysfunction to irreversible paralysis (Sahni, V. et al. (2010) Nature Reviews Neurology 6:363-372). 1,275,000 Americans suffer from some form of SCI (Paralysis Facts & FIGS. 2010) The Christopher and Dana Reeve Foundation Paralysis Resource Center) and, depending on the severity of injury and age at injury, lifetime healthcare costs associated with that injury may exceed 4.5 million dollars (Spinal Cord Injury Facts and Figures at a Glance (2012) J. Spinal Cord Med. 35:480-481). Stem cell therapy for SCI with a variety of cell sources has been investigated in numerous preclinical and a few clinical trials (Reier, P. J. (2004) NeuroRx: The Journal of the American Society for Experimental NeuroTherapeutics 1:424-451). Despite promising findings in predominantly rodent models (Lu, P. et al. (2012) Cell 150:1264-1273; Busch, S. A. et al. (2011) The Journal of Neuroscience: the Official Journal of the Society for Neuroscience 31:944-953; Parr, A. M. et al. (2007) Bone Marrow Transplantation 40:609-619), clinical trials have not yet substantiated the clinical utility of these stem cell therapies. This discrepancy has in part been linked to differences between rodent and higher order mammalian spinal cords, and differences in the severity or mechanism of SCI (Sahni, V. et al. (2010) Nature Reviews Neurology 6:363-372). As discussed below, Applicants' research on a congenital form of SCI is providing critical leads in the search for a clinically relevant, stem cell based therapy or cure for SCI.
Myelomeningocele (MMC), a form of spina bifida (SB), is a devastating birth defect caused by incomplete closure of the neural tube during development. Intrauterine damage to the exposed spinal cord leaves afflicted children with lifelong paralysis, fecal and urinary incontinence, musculoskeletal deformities and cognitive disabilities. Healthcare costs for children with MMC are 13 times greater than those for children without MMC. Even as adults, individuals born with MMC shoulder almost 7 times the medical expenses of peers with no history of MMC (Ouyang, L. et al. (2007) Birth Defects Research Part A: Clinical and Molecular Teratology. 79:552-558). In the US alone, approximately 4 children a day are born with this personally and financially costly disease (Parker, S. E. et al. (2010) Birth Defects Res. A Clin. Mol. Teratol. 88(12):1008-1016). The recent Management of Myelomeningocele Study (MOMS) randomized-controlled clinical trial demonstrated that in utero coverage of the spinal cord improves the paralysis of some MMC patients compared to postnatal repair (Adzick, N. S. et al. (2011) N. Engl. J. Med. 364:993-1004). While promising, these improvements were limited and sporadic. Covering the spinal cord may prevent further in utero damage, but simple closure fails to reverse injury incurred prior to repair. In utero stem cell therapy can build upon this surgical advance to cure MMC. The fetal environment contains numerous qualities which can facilitate stem cell therapy. (Tiblad, E. et al. (2008) Best Pract. Res Clin. Obstet. Gynaecol. 22(1):189-201; Flake, A. W. (2004) Best Pract. Res Clin. Obstet. Gynaecol. 18:941-958) Chief among them, the natural receptivity of the gestational environment to remodeling and regeneration of fetal tissues by stem cells. While a diverse array of autologous and allogeneic cells have been investigated for in utero therapy (Flake, A. W. et al. (1999) Blood 94:2179-2191; Roybal, J. L. et al. (2010) Semin. Fetal Neonatal. Med. 15:46-51; Fuchs, J. R. et al. (2003) J. Pediatr. Surg. 2003; 38:984-987; Fuchs, J. R. et al. (2005) Stem Cells 23:958-964; Fuchs, J. R. et al. (2004) J. Pediatr. Surg. 39:834-838; Kaviani, A. et al. (2003) J. Am. Coll. Surg. 196:592-597; Kaviani, A. et al. (2001) J. Pediatr. Surg. 36:1662-1665), substantive advances in cell therapy for MMC have not yet been made.
Thus, a need exists in the art for compositions and method to treat CSI and related disorders. This disclosure satisfies this need and provides related advantages as well.